The present invention relates to N-substituted derivatives of glutamic acid of pharmaceutical interest, to pharmaceutical compositions which include compounds of the invention and pharmaceutically acceptable carriers, to methods of their preparation, and to their use in purification of interleukin-1.beta. converting enzyme (ICE). The novel compounds of the present invention are inhibitors of ICE and hence are useful in controlling human disorders associated with generation of interleukin-1.beta. (IL-1.beta.), including but not limited to rheumatoid arthritis, inflammatory bowel disease, stroke, Alzheimer's disease, septic shock, and acute myelogenous leukemia.
ICE acts on pro-interleukin-1.beta. (pro-IL-1.beta.) to generate interleukin-1.beta. (IL-1.beta.) which is an inflammatory cytokine. Cleavage occurs between aspartate 116 and alanine 117 of pro-IL-1.beta.. The substrate specificity of ICE has been studied by P. R. Sleath, et al., in J. Biological Chem., 1990;265:14526-14528 and by D. K. Miller, et al., in Ann. NY Acad. Sci., 1993;696:133-48, who found ICE to be highly specific for aspartic acid residues at the P-1 position. Substitution of even highly similar amino acids such as glutamate or asparagine for aspartic acid at the P-1 position of decapeptides which span the ICE cleavage site in pro-IL-1.beta. were found to reduce the rate of cleavage to less than five percent of the native decapeptide with aspartic acid at P-1. This high substrate specificity allows ICE to recognize and cleave only pro-IL-1.beta. in vivo and hence inhibition of ICE would reduce or eliminate inflammatory reactions associated with excess ICE activity by preventing the formation of IL--.beta.. Conditions associated with excess ICE activity may include, but are not limited to joint inflammation such as in rheumatoid arthritis, gastrointestinal inflammation such as with inflammatory bowel disease, neuroinflammatory disorders such as seen in stroke and Alzheimer's disease, septic shock, and cancerous diseases such as acute myelogenous leukemia. ICE inhibitors have potential therapeutic utility in such conditions.
Many peptidic inhibitors of ICE have been described in the literature including tetrapeptide aldehydes such as Ac-Tyr-Val-Ala-AspCHO! by SEQ ID NO.1 K. T. Chapman in Bioorganic & Medicinal Chemistry Letters, 1992;2:613-618, tripeptide aldehydes and derivatives such as Cbz-Val-Ala-AspCHO! by T. L. Graybill, et al., in Int. J. Peptide Protein Res., 1994;44:173-182, peptidic acyloxymethyl ketone derivatives by R. E. Dolle, et al., in J. Medicinal Chemistry, 1994;37:563-564 and by C. V. C. Prasad, et al., in Bioorganic & Medicinal Chemistry Letters, 1995;5:315-318, and N-acyl-aspartic acid ketones by A. M. M. Mjalli, et al., in Bioorganic & Medicinal Chemistry Letters, 1995;5:1405-1408. In accordance with the substrate specificity of ICE, these previous disclosures focus on derivatives of aspartic acid as the preferred P-1 substituent. In the acyloxymethyl ketone papers by Dolle and Prasad, direct comparison of an acyloxymethyl ketone derived from aspartic acid to a similar compound derived from glutamic acid showed that, for ICE, the glutamic acid derived compound was "devoid of enzyme affinity" (quote from Dolle, et al., paper).
EP 0519748A discloses peptidyl derivatives as inhibitors of interleukin-1.beta. converting enzyme.
EP 0529713A discloses an affinity chromatography matrix useful in purifying interleukin-1.beta. converting enzyme.
EP 0547699A discloses peptidyl derivatives as inhibitors of interleukin-1.beta. converting enzyme.
However, the compounds disclosed in the above references do not disclose or suggest the ICE inhibitory activity of the compounds described hereinafter. On the contrary, they suggest that compounds of the present invention would be unlikely to contain significant ICE inhibitory activity.